Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California 92121, USA.
J Med Chem. 2009 Mar 12;52(5):1255-8. doi: 10.1021/jm8014537.
The HCV RNA-dependent RNA polymerase has emerged as one of the key targets for novel anti-HCV therapy development. Herein, we report the optimization of the dihydropyrone series inhibitors to improve compound aqueous solubility and reduce CYP2D6 inhibition, which led to the discovery of compound 24 (PF-00868554). Compound 24 is a potent and selective HCV polymerase inhibitor with a favorable pharmacokinetic profile and has recently entered a phase II clinical evaluation in patients with genotype 1 HCV.
丙型肝炎病毒（HCV）依赖 RNA 的 RNA 聚合酶已成为新型抗 HCV 治疗开发的关键靶点之一。在此，我们报告了二氢吡喃酮系列抑制剂的优化，以提高化合物的水溶性并降低 CYP2D6 抑制作用，从而发现了化合物 24（PF-00868554）。化合物 24 是一种有效的、选择性的 HCV 聚合酶抑制剂，具有良好的药代动力学特性，最近已进入基因 1 型 HCV 患者的 II 期临床评估。
